Brain bioenergetics and slow wave activity in first episode psychosis

首发精神病中的脑生物能学和慢波活动

• 批准号: 10418621
• 负责人: Abdullah Cagri Yuksel
• 金额: $ 17.05万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418621
• 关键词: Antipsychotic Agents; Biochemical; Bioenergetics; Biological; Biological Process; Bipolar Disorder; Brain; Cells; Cellular biology; Characteristics; Chronic Schizophrenia; Consumption; Coupled; Creatine Kinase; Data; Development Plans; Disease; Early Intervention; Electroencephalography; Energy Metabolism; Energy-Generating Resources; Enzymes; Frequencies; Funding; Glucose; Glutamates; Goals; Grant; Homeostasis; Impaired cognition; Impairment; Intermediate Variables; Intervention; Laboratories; Link; Measures; Mediating; Mediator of activation protein; Mentorship; Metabolic; Metabolism; Mitochondria; Modality; Molecular; Morbidity - disease rate; Natural regeneration; Neurons; Occipital lobe; Organ; Outcome; Oxidative Phosphorylation; Oxygen; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorus; Photic Stimulation; Play; Polysomnography; Process; Psychiatrist; Psychotic Disorders; Reaction; Research; Research Personnel; Rest; Role; Schizophrenia; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Structure; Synapses; Techniques; Testing; Time; Training; Treatment Failure; Writing; brain abnormalities; career development; density; experimental study; first episode psychosis; frontal lobe; functional decline; improved; in vivo; information processing; inorganic phosphate; neuroimaging; neurotransmission; non rapid eye movement; non-affective psychoses; novel; novel strategies; partial response; preservation; response; severe psychiatric disorder; side effect; skills; sleep abnormalities; statistics; targeted treatment

ABSTRACT Schizophrenia (SZ) is a common and severe psychiatric disorder. There is emerging evidence that multiple structural and functional brain abnormalities develop early in the illness and outcomes can improve significantly with early intervention as opposed to reversal of morbidity. However, all currently available antipsychotics are effective on similar pathways; treatment failure is common and patients frequently suffer from side effects. Therefore, there is a critical need to identify new biological mechanisms that contribute to the pathology early in the illness and to develop novel treatments targeting these processes. Integrity of the high energy phosphate (HEP) metabolism is essential for providing energy required by myriad neuronal functions, including neurotransmission and plasticity -processes implicated in SZ pathology. While ATP is the primary energy source, creatine kinase (CK) enzyme reaction plays a central role in maintaining stable ATP concentrations by creating a HEP pool as PCr, and generating ATP from PCr during increased energy demand. Recent studies show abnormalities in several bioenergetic mechanisms in psychotic disorders, including reductions in CK rate at rest. However, CK has not been studied during neuronal activation in psychotic disorders. Identifying mediators of brain energy abnormalities will allow novel treatment approaches. Sleep, and specifically slow wave sleep (SWS), has a restorative role in brain energy homeostasis, and EEG power density at the slow wave frequency (slow wave activity, SWA) is the measure associated with the improvements in energy measures. SZ is characterized by pervasive sleep disturbances, including in the first episode (FE), and there is evidence for specific SWS deficits. However, the association of sleep characteristics and brain energy metabolism in this disorder has not been studied. Given this background, we propose to study the activity of CK enzyme during neuronal activation in patients with FE non-affective psychosis, and identify the role of reduced overnight accumulation of SWA in explaining CK modulation. For this purpose, we will collect overnight polysomnography data and use in vivo phosphorus magnetization transfer. Candidate is a psychiatrist with a background in neuroimaging research in psychotic disorders. Training objectives for this grant are for the candidate to gain 1. Training in sleep research; 2. Advanced training in cell biology and biochemical aspects of brain function; 3. Advanced training in statistics; 4. Training in data presentation and grant writing skills. These goals will be accomplished by mentorship, formal coursework, and the help of an exceptionally-qualified team of advisors and collaborators. The successful completion of this career development plan will assist the candidate in making the transition to an independent investigator with R01 level funding.

抽象的 精神分裂症（SZ）是一种常见且严重的精神疾病。有新兴的证据表明 多重结构和功能性脑异常在疾病早期发展，结果可以改善 与发病率逆转相比，早期干预非常重要。但是，所有当前可用 抗精神病药在类似的途径上有效。治疗失败很常见，患者经常遭受 副作用。因此，迫切需要确定新的生物学机制有助于 病理学早期的病理，并开发针对这些过程的新型治疗方法。 高能磷酸盐（HEP）代谢的完整性对于提供提供的能量至关重要 无数神经元功能，包括神经传递和可塑性 - 涉及SZ病理学的过程。 而ATP是主要能源，而肌酸激酶（CK）酶反应在维持中起着核心作用 通过将HEP池作为PCR创建稳定的ATP浓度，并在增加能量期间从PCR产生ATP 要求。最近的研究表明，精神疾病的几种生物能机制异常， 包括静止时CK率的降低。但是，在精神病中神经元激活期间尚未研究CK 疾病。 识别脑能量异常的介体将允许新的治疗方法。睡觉，然后 特别是慢波睡眠（SWS），在大脑能量稳态中具有恢复性作用，而脑电图密度 在慢波频率下（慢波活动，SWA）是与改进相关的度量 能源度量。 SZ的特征是普遍的睡眠障碍，包括在第一集（Fe）和 有证据表明特定的SWS缺陷。但是，睡眠特征与大脑能量的关联 尚未研究这种疾病中的代谢。 鉴于此背景，我们建议研究CK酶在神经元激活中的活性 有Fe非感染精神病的患者，并确定SWA过夜积累的作用 解释CK调制。为此，我们将收集隔夜多渗透学数据并在体内使用 磷磁化转移。 候选人是一名精神科医生，具有神经影像学研究的背景精神病研究。训练 这笔赠款的目标是候选人获得1个。睡眠研究的培训； 2。高级培训 细胞生物学和脑功能的生化方面； 3。统计的高级培训； 4。培训 数据表现和授予写作技巧。这些目标将通过指导，正式实现 课程工作，以及一个顾问和合作者团队的帮助。成功 该职业发展计划的完成将有助于候选人过渡到独立 R01级资金的研究人员。